Structure and different conformational states of native AMPA receptor complexes
Structure and different conformational states of native AMPA receptor complexes
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DOI：
10.1038/nature03328
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发表时间：
2005-02-03
期刊：
影响因子：
64.8
通讯作者：
Walz, T
中科院分区：
文献类型：
--
作者：
Nakagawa, T;Cheng, YF;Walz, T
离子型谷氨酸受体介导中枢神经系统中的快速兴奋性突触传递（1，2）。它们的调节被认为会影响学习和记忆，并且它们的功能障碍与神经和精神疾病的发病机制有关（1，2）。尽管有丰富的功能数据，但对这些配体门控离子通道的完整三维结构知之甚少。在这里，我们提出了天然AMPA受体（α-氨基-3-羟基-5-甲基-4-异恶唑丙酸; AMPA-Rs）纯化的大鼠大脑的结构，通过单粒子电子显微镜测定。与同源四聚体重组GluR 2（参考文献3）不同，天然异源四聚体AMPA-R采用了各种构象，这主要反映了两个二聚体胞外氨基末端结构域的可变分离。跨膜蛋白的stargazin/ TARP家族的成员与AMPA-R共纯化，并有助于代表复合物的跨膜区域的密度。谷氨酸和环噻嗪显着改变的通道复合物的构象平衡，这表明脱敏与分离的N-末端结构域。这些数据提供了一个重要的配体门控离子通道的大脑的构象变化的一瞥。
Ionotropic glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system(1,2). Their modulation is believed to affect learning and memory, and their dysfunction has been implicated in the pathogenesis of neurological and psychiatric diseases(1,2). Despite a wealth of functional data, little is known about the intact, three-dimensional structure of these ligand-gated ion channels. Here, we present the structure of native AMPA receptors (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; AMPA-Rs) purified from rat brain, as determined by single-particle electron microscopy. Unlike the homotetrameric recombinant GluR2 (ref. 3), the native heterotetrameric AMPA-R adopted various conformations, which reflect primarily a variable separation of the two dimeric extracellular amino-terminal domains. Members of the stargazin/ TARP family of transmembrane proteins co-purified with AMPA-Rs and contributed to the density representing the transmembrane region of the complex. Glutamate and cyclothiazide markedly altered the conformational equilibrium of the channel complex, suggesting that desensitization is related to separation of the N-terminal domains. These data provide a glimpse of the conformational changes of an important ligand-gated ion channel of the brain.